Effects of lovastatin on breast cancer cells: a proteo-metabonomic study.
Effects of lovastatin on breast cancer cells: a proteo-metabonomic study.
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洛伐他汀对乳腺癌细胞的影响：一项蛋白质代谢研究。
DOI：
10.1186/bcr2485
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发表时间：
2010
影响因子：
7.4
通讯作者：
Klawitter, Jost
中科院分区：
文献类型：
--
作者：
Klawitter, Jelena;Shokati, Touraj;Moll, Vanessa;Christians, Uwe;Klawitter, Jost
他汀类药物是具有多种活性的降胆固醇药物，包括抑制异戊二烯化和减少驱动细胞增殖和生存反应的信号。在这项研究中，我们利用蛋白质组学和代谢组学分析技术的组合评估了洛伐他汀酸和内酯对乳腺癌MDAMB231和MDAMB468细胞的影响。洛伐他汀抑制乳腺癌细胞系的增殖。MDAMB231细胞对其作用更敏感，在大多数情况下，洛伐他汀酸比洛伐他汀内酯在操纵蛋白表达方面表现出更强的效力。Rho抑制剂GDI-2的表达增加稳定了非活性Ras同源基因家族成员A (RhoA)，导致其活性膜结合形式的表达减少。其下游靶点cofilin、CDC42和G3BP1是受洛伐他汀影响的GTPase家族的成员。我们的数据表明洛伐他汀通过调节禁止蛋白和视网膜母细胞瘤（Rb）的表达来调节e2f1通路。这随后导致e2f下游靶点小染色体维持蛋白7 （MCM7）和MutS同源物2 （MSH2）的变化。洛伐他汀也调节akt信号通路。磷酸酶和紧张素同源物（PTEN）的增加和DJ-1表达的减少导致活性pAkt的下调。洛伐他汀参与akt信号通路是通过其下游靶点肿瘤进展因子NDRG1的上调来证实的。洛伐他汀暴露的代谢后果包括糖酵解和克雷布斯循环活性的抑制，以及脂质生物合成。蛋白质组学和代谢组学的结合使我们能够确定洛伐他汀抗肿瘤活性的几个关键靶点。我们的研究结果表明洛伐他汀有可能减少乳腺癌细胞的生长。
Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation and reduction of signals driving cell proliferation and survival responses. In this study we evaluated the effects of lovastatin acid and lactone on breast cancer MDAMB231 and MDAMB468 cells using a combination of proteomic and metabonomic profiling techniques. Lovastatin inhibited proliferation of breast cancer cell lines. MDAMB231 cells were more sensitive to its effects, and in most cases lovastatin acid showed more potency towards the manipulation of protein expression than lovastatin lactone. Increased expression of Rho inhibitor GDI-2 stabilized the non-active Ras homolog gene family member A (RhoA) leading to a decreased expression of its active, membrane-bound form. Its downstream targets cofilin, CDC42 and G3BP1 are members of the GTPase family affected by lovastatin. Our data indicated that lovastatin modulated the E2F1-pathway through the regulation of expression of prohibitin and retinoblastoma (Rb). This subsequently leads to changes of E2F-downstream targets minichromosome maintenance protein 7 (MCM7) and MutS homolog 2 (MSH2). Lovastatin also regulated the AKT-signaling pathway. Increased phosphatase and tensin homolog (PTEN) and decreased DJ-1 expression lead to a down-regulation of the active pAkt. Lovastatin's involvement in the AKT-signaling pathway was confirmed by an upregulation of its downstream target, tumor progressor NDRG1. Metabolic consequences to lovastatin exposure included suppression of glycolytic and Krebs cycle activity, and lipid biosynthesis. The combination of proteomics and metabonomics enabled us to identify several key targets essential to the antitumor activity of lovastatin. Our results imply that lovastatin has the potential to reduce the growth of breast cancer cells.
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影响因子：
3.5
作者：
Cauley, JA;Zmuda, JM;Bauer, DC
通讯作者：
Bauer, DC
影响因子：
3.3
作者：
Davidson, Ben;Hadar, Rivka;Reich, Reuven
通讯作者：
Reich, Reuven
DOI：
10.1080/10253890701314863
发表时间：
2007-11-01
影响因子：
2.3
作者：
Gesualdi, N. Montesano;Chirico, G.;Esposito, F.
通讯作者：
Esposito, F.
影响因子：
7.4
作者：
Havlis, J;Thomas, H;Shevchenko, A
通讯作者：
Shevchenko, A
影响因子：
4.3
作者：
JavanMoghadam-Kamrani, Sonia;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan